Malignancy is a common and dreaded complication following organ transplantation (References 1-4). The high incidence of neoplasms and its aggressive progression, which are associated with immunosuppressive therapy, has been thought to be due to the resulting impairment of the organ graft recipient""s immune surveillance system.
Cyclosporine, a cyclic peptide (also known as cyclosporin A or CsA) and the macrolide FK506 (tacrolimus) are well known and widely used immunosuppressants for transplant recipients and autoimmune patients. Cyclosporine has had major impact on improving patient outcome following organ transplantation (References 4 and 5). Drugs typically employed as immunosuppressive agents include cyclosporine, azathioprine, leflunomide, rapamycin and other FKBP targeted compounds including dexamethasone; also included in this group are steroids (including corticosteroids), antilymphocyte globulins, and monoclonal anti-T cell antibodies.
A surprising mechanism for the heightened malignancy that is independent of host immunity has been discovered. In a co-filed application entitled xe2x80x9cUse of TGF-xcex2 antagonists to inhibit tumor cell formation or progressionxe2x80x9d the present inventors, et al., have disclosed that TGF-xcex2 antagonists are effective in reducing or eliminating the incidence of neoplasms mentioned above. Herein yet further methods and compositions comprising angiotensin II inhibitors useful for preventing or overcoming these complications are provided.
Angiotensin II is an octapeptide biological signaling molecule produced from the decapeptide precursor, angiotensin I by the action of an enzyme: Angiotensin coverting enzyme (ACE). Angiotensin I itself is produced from the protein angiotensinogen circulating in plasma by the action of the enzyme Renin. These molecules form part of the signaling pathway involved in the homeostatic regulation of blood volume. This regulation of blood pressure is reflected in changes in blood pressure, administration of angiotensin II mediates a wide range of biological changes, including vasoconstriction and a consequent increase in blood pressure. For this reason angiotensin II inhibitors are commonly used clinically to control high blood pressure.
The present invention addresses the need for immunosupressive therapies that confer a lower risk of malignancies associated with treatment.
The invention provides methods for reducing formation or progression of neoplasms associated with immunosuppressive therapy in a mammal. The methods include treatment of the mammal with an effective amount of an angiotensin II inhibitor.
Also provided are compositions for use in these methods. The compositions comprise an effective amount of an angiotensin II inhibitor and an immunosuppressive agent.
The invention also provides alternative methods of treatment for reducing formation or progression of a neoplasm in a mammal. The method includes treating the mammal with an effective amount of an angiotensin II inhibitor, where the treatment is not part of a chemotherapy regimen or a radiation therapy treatment regimen.
In addition, the invention provides methods for identifying angiotensin II inhibitor compounds capable of inhibiting the formation or proliferation of tumors in a mammal undergoing immuno-suppressive therapy. These methods comprise: first providing a test mammal with a tumor cell; second, treating the test animal with an immunosuppressive agent in an immunosuppressive regimen, followed by administering the angiotensin II inhibitor candidate to the test mammal; third, monitoring the growth of the tumor cell in the test mammal; and then comparing the growth of the tumor cell in the test animal with the growth of a tumor cell in a control animal undergoing an identical immunosuppressive regimen, but which has not been treated with the angiotensin II inhibitor test compound.